Methyl p-hydroxyphenyllactate and nuclear type II binding sites in malignant cells: metabolic fate and mammary tumor growth.
Previous studies in our laboratory demonstrated that methyl p-hydroxyphenyllactate (MeHPLA) is an important cell growth-regulating agent which binds to nuclear type II binding sites in normal and malignant cells. Furthermore, this compound is deficient in a variety of rat and mouse mammary tumors and human breast cancer preparations, and this deficiency correlates with the loss of regulatory control. The present studies were performed to examine the metabolic fate of [3H]MeHPLA in mouse mammary tumors. Stable analogs of this compound such as 4,4'-dihydroxy benzylidene acetophenone were also assessed for nuclear type II site binding affinity and their ability to inhibit mammary cancer cell growth and proliferation in vitro and in vivo. The results demonstrate that mouse mammary tumors contain esterase activity which hydrolyzes MeHPLA to p-hydroxyphenyllactic acid, and this was the only major metabolite detected in these tumor preparations in vitro or in vivo. 4,4'-Dihydroxy benzylidene acetophenone, an esterase-stable MeHPLA analog, was found to bind with high affinity to nuclear type II sites but not the estrogen receptor, was capable of occupying type II sites in cultured MCF-7 cells, and inhibited the proliferation of these cells in concentrations which directly correlated with type II binding site occupancy. Similarly, 4,4'-dihydroxy benzylidene acetophenone administration by silastic implant or injection resulted in a dose-dependent inhibition of the growth of transplantable mammary tumors in mice, suggesting that this stable analog mimicks MeHPLA as a cell growth-regulating agent. Taken together, these results suggest esterase hydrolysis of MeHPLA in mammary tumors may result in a deficiency in this compound which correlates with a loss of regulatory control.
Markaverich
B M
BM
Center for Biotechnology, Baylor College of Medicine, The Woodlands, Texas 77381.
Gregory
R R
RR
Alejandro
M
M
Kittrell
F S
FS
Medina
D
D
Clark
J H
JH
Varma
M
M
Varma
R S
RS
D000818:Animals; D001667:Binding, Competitive; D001943:Breast Neoplasms / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism*; D002599:Chalcone / Q000031:analogs & derivatives / Q000378:metabolism*; D047188:Chalcones; D003600:Cytosol / Q000201:enzymology / Q000378:metabolism; D004950:Esterases / Q000378:metabolism; D005260:Female; D006801:Humans; D007773:Lactates / Q000378:metabolism*; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D011427:Propiophenones / Q000378:metabolism*; D011959:Receptors, Estradiol / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000378:metabolism
D047188:Chalcones; D007773:Lactates; D011427:Propiophenones; D011959:Receptors, Estradiol; C055915:methyl 4-hydroxyphenyllactate; D002599:Chalcone; C007423:4,4'-dihydroxychalcone; D004950:Esterases